Tremendous progress in the past few years has led to the identification of several circadian clock genes. This now makes it possible to determine how alterations of human circadian clock genes, and their expression, could lead to differences in circadian and sleep/wake cycle phenotypes. Of particular interest for understanding genetics of the human circadian system are individuals with sleep phase disorders, such as delayed sleep phase syndrome (DSPS) and advanced sleep phase syndrome (ASPS), because recent studies indicate a genetic basis for these disorders. While it is assumed that both ASPS and DSPS are disorders of circadian timing, little is known about how the circadian clock system, or its interaction with sleep processes, are affected in these individuals. Therefore, one of the overall objectives of the proposed studies is to determine the properties (e.g., phase, amplitude, and period) of circadian rhythms under entrained and constant routine conditions in familial ASPS or DSPS. A second objective is to test hypotheses that could explain the mechanisms (i.e., response to light, alterations in period) that underlie the phase disturbance in these conditions. Although it is commonly assumed that sleep per se is normal in the circadian sleep phase disorders, there is some evidence to suggest that the regulation of sleep homeostasis may be altered in DSPS. Therefore, a third specific aim of the proposed studies is to define the sleep-wake characteristics via EEG/polysomnography in DSPS and ASPS subjects during baseline sleep and recovery sleep following sleep deprivation in which the subjects are allowed to begin recovery sleep at a normal or an abnormal circadian time. The approach of studying familial DSPS and ASPS provides a unique opportunity to clearly define circadian and sleep phenotypes in individuals whose sleep/wake cycle is due to intrinsic biological changes and not merely a result of environmental influences and societal pressures. The results of these studies are expected to not only lead to new insights into the regulation of sleep and circadian rhythms in humans, but also to new therapeutic approaches for the treatment of sleep/wake cycle disorders.